Abstract
ABSTRACTEpidemiological research has shown that elevated serum urate concentration is a risk factor for the development of kidney disease; however, the mechanisms underlying this process have not yet been elucidated. To examine the role of urate in the kidney, we used Wistar rats to functionally disrupt expression of urate oxidase (UOX) by using the CRISPR/Cas9 system. In comparison to wild-type (WT) rats, serum urate levels spontaneously and persistently increased in UOX-KO rats, without showing a significant decrease in survival rate. Architecture and function of the kidneys in UOX-KO rats were impaired. Injury to the kidney resulted in increased interstitial fibrosis, macrophage infiltration, increased expression of NLRP3 and IL-1β, and activation of multiple cell-signaling pathways associated with autophagy, such as AMPK, p38 MAPK, ERK and JNK pathways. Inhibition of autophagy with the PI3K inhibitor 3-MA abrogated the development of kidney damage and attenuated renal fibrosis, macrophage infiltration, and expression of NLRP3 and IL-1β in injured kidneys. In conclusion, the UOX-KO rat is a great model to study hyperuricemia-related diseases. Hyperuricemia-induced autophagy and NLRP3-dependent inflammation are critically involved in the development of renal damage and, therefore, highlight the inhibition of autophagy and inflammation in search of therapeutic strategies to treat uric acid nephropathy.
Highlights
Hyperuricemia is a metabolic disease caused by abnormalities in purine metabolism, mainly due to the increased formation or reduced excretion of urate
Hyperuricemia is critically associated with chronic kidney injury and the prevalence of uric acid nephropathy (UAN) has increased worldwide
KO of the Uox gene in rats resulted in spontaneously sustained high serum uric acid levels and severe nephropathy, characterized by increased blood urea nitrogen (BUN) and creatinine levels, increased levels of urinary volume and proteins, renal fibrosis and inflammatory cell infiltration in the kidney
Summary
Hyperuricemia is a metabolic disease caused by abnormalities in purine metabolism, mainly due to the increased formation or reduced excretion of urate. Two-thirds of the urate produced in humans is excreted by the kidneys. Reabsorption and secretion in the renal proximal. M.W., 0000-0003-4233-8184; Y.M., 0000-0002-9167-9607; X.C., 0000-00015315-8555; N.L., 0000-0002-6351-0599; S.Q., 0000-0003-0811-7070; H.C., 00000002-2259-5522 An increasing number of experimental and epidemiological studies have suggested that uric acid is an independent risk factor for renal disease (Mallat et al, 2016; Obermayr et al, 2008). The mechanisms underlying uric acid nephropathy (UAN) remain incompletely understood
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